We have investigated the immunopathogenic mechanisms responsible for CD4+ T-cell depletion. Apoptosis intensity is 3- to 4-fold higher in lymph nodes of HIV-infected individuals compared to those of HIV-uninfected individuals. Generally, all compartments of the lymph node are involved in the apoptosis phenomenon in HIV-infected lymph nodes. Apoptosis correlates with the degree of activation of the lymphoid tissue and the chronic immune activation associated with HIV infection. In late stages of HIV disease, apoptosis occurs with similar intensity but in different compartments. Apoptosis does not correlate with progression of the disease (i.e., CD4+ T-cell count) or with viral burden. All lymphocyte subsets (B and T cells, CD4+ and CD8+) have been shown to undergo apoptosis. The importance of cell activation in HIV infection is underscored by the observation that cyclosporin A (CsA), inhibits HIV infection in vitro (60% to 80%). CsA has been shown to modulate a series of parameters during primary infection in SIV-infected monkeys. CsA administration delays onset of viremia, prevents a drop in CD4+ T cells and an increase in CD8+ T lymphocytes, increases antibody response, and decreases apoptosis intensity in lymph node.